Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[CH:11]=[C:12]([C:17]([O:19]CC)=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2].C1COCC1.O.[OH-].[Li+]>CO>[CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCNc1nccc(-c2cc(C(=O)OCC)c(=O)[nH]n2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCNc1nccc(-c2cc(C(=O)O)c(=O)[nH]n2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 400 mg of ethyl 6-(2-ethylaminopyrimidin-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate, 2 ml of THF, 2 ml of water, 2 ml of methanol and 100 mg of lithium hydroxide is stirred at room temperature for 1 hour, and the volatile constituents are removed in vacuo. A pH of 4 is adjusted by dropwise addition of 2N hydrochloric acid, and the precipitate which has formed is filtered off with suction, stirred with 10 ml of isopropanol and filtered off with suction and dried.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(O)(=O)C.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([NH:4][CH:19]1[CH2:20][CH2:21][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:17][CH2:18]1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C=CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C=CCNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
Allylamine (0.45 mL, 0.34 g, 6.0 mmol), acetic acid (0.300 mL, 315 mg, 5.24 mmol), and 3 Å molecular sieves (2.00 g) were added to a solution of 1-(t-butoxycarbonyl)-4-piperidone (1.00 g, 5.01 mmol) in 14 mL of 1,2-dichloroethane. After stirring 0.5 h at rt, sodium triacetoxyborohydride (1.62 g, 7.6 mmol) was added in two portions 5 min apart. After an additional 3 h, the mixture was partitioned between 30 mL of ethyl acetate and 20 mL of saturated aqueous sodium bicarbonate. The aqueous layer was extracted with 30 mL of ethyl acetate and the organic layers were washed in succession with 20 mL of brine, combined, dried over sodium sulfate, and evaporated to give 1.20 g of crude 4-(allylamino)-1-(t-butoxycarbonyl)piperidine as a yellow syrup.
Reaction SMILES: C([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1)C1C=CC=CC=1.[C:18]([O-:21])([O-])=O.[K+].[K+].[Br:24][CH:25](Br)[CH3:26]>CN(C=O)C.CCOCC>[Br:24][CH2:25][CH2:26][O:14][C:11]1[CH:12]=[CH:13][C:8]([O:21][CH2:18][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:9][C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(Br)Br
Reactant: O=[N+]([O-])c1cc(Cc2ccccc2)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1OCCBr
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 139.3 %

Procedure:
A mixture of 4-benzyl-2-nitrophenol (1.3 g, 5.3 mmol) and K2CO3 (1.2 g, 8.7 mmol) in DMF (10 mL) was stirred for 10 min. Dibromoethane (1.4 mL, 16.2 mmol) was added to the reaction mixture and heated at 70° C. for 24 hrs. The reaction mixture was diluted with ether (30 mL) and washed with water (20 mL) and brine (20 mL). The ether layer was dried (MgSO4) and concentrated under reduced pressure. The crude product was fractionated by flash chromatography (4:1 hexane/ethyl acetate) yielding bromoethane 6 as a yellow oil (1.3 g, 88%). 1H NMR: 3.65 (t, J=5 Hz, 2H), 4.35 (t, J=5 Hz, 2H), 5.05 (s, 2H), 7.0-7.5 (m, 8H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:17][CH:13]2[CH2:14][CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:12]2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: O=C(OCc1ccccc1)N1CCCC(O)C1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2OC2CCCN(C(=O)OCc3ccccc3)C2)CC1
Reaction time: 8 h
Yield: 58.7 %

Procedure:
3-Hydroxy-piperidine-1-carboxylic acid benzyl ester (2.34 g, 8.6 mmol) was dissolved in THF (40 mL) at r.t. 4-(2-Hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (2.4 g, 8.6 mmol) and triphenylphosphine (2.7 g, 10.32 mmol) were added. Diisopropyl azodicarboxylate (2.05 mL, 10.32 mmol) was added dropwise to the solution. The mixture was stirred overnight, and then concentrated under reduced pressure and purified using silica gel chromatography (100% ethyl acetate) to afford the title compound (2.5 g, 55%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[N:12]=[C:11]2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[OH-].[Na+].Cl>O1CCCC1.O.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[N:12]=[C:11]2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)c1cn(-c2cccc(OCC)c2)c(-c2ccc(F)cc2F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cccc(-n2cc(C(=O)O)nc2-c2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.10 g (0.27 mmol) of ethyl 1-(3-ethoxyphenyl)-2-(2,4-difluorophenyl)-1H-imidazole-4-carboxylate in 2 mL of tetrahydrofuran, 1 mL of water and 1 mL of methanol was added 0.20 mL (1.0 mmol) of 5.0 M NaOH solution. The reaction mixture was stirred at ambient temperature for 4 hrs. Hydrochloric acid (2.0 M) was then added to neutralize the reaction mixture. After removal of the organic solvents in vacuo, dichloromethane (10 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (5 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a yellow foam. LC/MS 345.0 (M+1).
Reaction SMILES: [CH2:1]([Br:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>C(C(C)=O)C>[Br-:8].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][C:21]1[CH:22]=[N+:23]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc2[nH]cc(Cc3cccnc3)c2c1
Solvent: CCC(C)=O
Product: COc1ccc2[nH]cc(Cc3ccc[n+](Cc4ccccc4)c3)c2c1
Product: [Br-]

Procedure:
Benzyl bromide (8.7 ml; 0.073 mol) was added to a stirring mixture of compound of Description 1 [5-methoxy-3-(pyridin-3-ylmethyl)-1H-indole] (3.5 g; 0.0146 mol) in methyl ethyl ketone (70 ml). The reaction mixture was refluxed for 3 hours. The product precipitated as a yellow solid was filtered and washed with diethyl ether and dried under vacuum. The compound was used as such without further purification.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([OH:16])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>C(#N)C>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][CH:4]([C:14]([NH:32][CH:29]2[CH2:31][CH2:30]2)=[O:16])[CH2:3]1
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Reactant: NC1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: O=C(NC1CC1)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 18 h
Yield: 94.5 %

Procedure:
To a solution of 16.4 g (75 mmole) of 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 ml of acetonitrile was added 13.8 g (85 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60° C. for one hour, cooled to room temperature and treated with 4.85 g (85 mmole) of cyclopropylamine. The reaction was stirred at room temperature for 18 hours, the solvent removed in vacuo and the residue partitioned between chloroform and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 18.3 g of 5-oxo-1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinecarboxamide, mp 94-96° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.F[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1>CN(C)C=O.O>[OH:10][C:4]1([CH2:3][CH2:2][OH:1])[CH2:9][CH2:8][N:7]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:28])([F:30])[F:29])[CH:20]=2)[CH2:6][CH2:5]1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: OCCC1(O)CCNCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(N2CCC(O)(CCO)CC2)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
To a solution of compound 26 (517 mg, 3.25 mmol) in anhydrous dimethylformamide (15 mL) under argon were added triethylamine (1.32 g, 13.0 mmol) and 4-fluoro-2-trifluoromethylbenzonitrile (1.80 g, 9.52 mmol). The solution was stirred at 80° C. for 4 hrs. The solution was cooled at room temperature and poured in water (100 mL), extracted with diethyl ether (3×25 mL), washed with brine and finally dried over magnesium sulphate. Purification of the resulting crude product by flash chromatography using ethyl acetate/hexane (7:3) as an eluant gave the desired compound 27a (687 mg, 68%). 1H NMR (400 MHz, Acetone-d6) δ: 1.74 (m, 6H), 3.45 (m, 2H), 3.85 (m, 4H), 7.24 (dd, 1H, J1=6.4 Hz, J2 =2.5 Hz), 7.32 (d, 1H, J=2.4 Hz), 7.72 (d, 1H, J=8.8 Hz).
Reaction SMILES: [O:1]=[O+][O-].[CH:4]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:10]=[CH:9][C:8]=1[OH:21])=CC>C(O)(=O)C.C(OCC)(=O)C>[OH:21][C:8]1[CH:9]=[CH:10][C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:12][C:7]=1[CH:4]=[O:1]
Reactant: CC=Cc1cc(Oc2ccccc2Cl)ccc1O
Reactant: O=[O+][O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=Cc1cc(Oc2ccccc2Cl)ccc1O

Procedure:
Ozone gas was introduced into a solution of 2-(1-propenyl)-4-(2-chlorophenoxy)phenol (14.5 g) in a mixture of acetic acid (10 ml) and ethyl acetate (150 ml) with stirring at 2°-7° C. for an hour. After removing of the excess of ozone gas and addition of aqueous solution of sodium dithionite, the organic layer was separated, washed with saturated aqueous sodium bicarbonate and water, dried and evaporated. The residue was purified by column chromatography (silical gel, benzene) to give oily 2-hydroxy-5-(2-chlorophenoxy)benzaldehyde (10.4 g).
Reaction SMILES: O=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH2:11]([NH2:15])[CH2:12][CH2:13][CH3:14].[Cl:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21]>>[Cl:16][CH2:17][CH2:18][NH:19][C:20]([N:15]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@H:3]1[OH:4])=[O:21]
Reactant: O=C=NCCCl
Reactant: CCCCN
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Product: CCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 80.5 %

Procedure:
3.0 g of D-ribose, 1.9 g of n-butylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5-(1). 5.0 g of 1-(2-chloroethyl)-3-n-butyl-3-D-ribofuranosylurea are thereby obtained as colorless caramel.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].N([O-])=O.[Na+].S(=O)(=O)(O)N.C1(C)C=CC=CC=1.[ClH:35]>C(O)(=O)C.O>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([S:8][C:6]2[CH:5]=[CH:4][C:3]([N+:16]([O-:18])=[O:17])=[C:2]([Cl:35])[CH:7]=2)=[CH:10][CH:11]=1
Reactant: Cl
Reactant: Nc1cc(Sc2ccc(Br)cc2)ccc1[N+](=O)[O-]
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(Sc2ccc(Br)cc2)cc1Cl

Procedure:
A solution of 2-amino-4-(4-bromophenylthio)nitrobenzene (Method 15) (2.25 g) in warm glacial acetic acid (13 ml) was poured onto ice (20 ml). Concentrated hydrochloric acid (3.95 ml) was added and the mixture was stirred and cooled to <5° C. A solution of sodium nitrite (0.524 g) in water (5 ml) was added over 7 minutes and the mixture was stirred for 2 hours at 0-5° C. Aqueous sulphamic acid solution (10% w/v) was added until a negative starch iodide test was observed. Meanwhile toluene was added to a solution of cuprous chloride (0.745 g) in water (1 ml) and concentrated hydrochloric acid (1.15 ml) and the mixture was cooled to <0° C. The first preparation (diazonium salt) was then added to the cold cuprous chloride mixture over 5 minutes and the resultant mixture was stirred at ambient temperature for 18 hours. The organic layer was separated and the aqueous layer was extracted with toluene (3×10 ml). The organic extracts were combined, washed with water and brine then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-15% ethyl acetate/hexane to give the title compound (0.644 g). MS: 343 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:22]#[CH:23])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13]2([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26](=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:22]#[C:23][C:31]2[CH:32]=[CH:33][C:28]([CH2:27][C:26]([O:25][CH3:24])=[O:35])=[CH:29][CH:30]=2)[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13]2([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(C(=O)OC(C)(C)C)c2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)Cc1ccc(C#Cc2cc(C(=O)OC(C)(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following General Procedure B and using 6-ethynyl-2,2,4,4-tetramethylchroman-8-carboxylic acid tert-butyl ester (Intermediate 52, 0.051 g, 0.16 mmol), 4-iodo phenyl acetic acid methyl ester (0.053 g, 0.19 mmol), triethyl amine (3 mL), copper(I)iodide (0.02 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.03 g, 0.043 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 20% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow oil (0.014 g, 19%).
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH:12]1[CH2:18][CH2:17][CH2:16][C@H:13]1[CH2:14][OH:15].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:1]([N:12]1[CH2:18][CH2:17][CH2:16][C@H:13]1[CH2:14][OH:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC[C@@H]1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A solution of carbobenzoxychloride 7.87 g in methylene chloride 50 ml is dropped to a mixture of L-prolinol 4.9 g in methylene chloride 50 ml and sodium hydrogen carbonate 11.6 g in water 50 ml at 0° C. under vigorously agitation. The mixture is stirred for 1 hour at room temperature. The organic layer is separated, washed, dried and concentrated in vacuo to give N-carbobenzoxy-L-prolinol 10.25 g.
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@H:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].[OH-].[Na+].Br[CH2:16][C:17]1[C:18]([F:30])=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][C:22]=1[F:23].N12CCN(CC1)CC2>CCCCCCC.O.C(#N)C>[Cl:1][C:2]([Cl:12])=[CH:3][CH:4]1[CH:6]([C:7]([O:9][CH2:16][C:17]2[C:18]([F:30])=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=[CH:21][C:22]=2[F:23])=[O:8])[C:5]1([CH3:10])[CH3:11]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Reactant: Fc1ccc(-c2ccccc2)c(F)c1CBr
Agent: C1CN2CCN1CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CCCCCCC
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OCc1c(F)ccc(-c2ccccc2)c1F

Procedure:
To a mixture of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid (2.2 g, 0.11 mole) in 75 ml of heptane was added sodium hydroxide (0.42 g, 0.011 mole) in 5 ml of water. The mixture was shaken until the acid dissolved. The water was then removed by distillation, the volume of the reaction mixture being reduced to 50 ml. To the reaction mixture was added 3-bromomethyl-2,4-difluoro[1,1'-biphenyl] (3.0 g, 0.011 mole) and 0.1 gram of 1,4-diazabicyclo[2.2.2]octane in 35 ml of acetonitrile. The mixture was heated under reflux for 3 hours. The solvent was then removed by evaporation under reduced pressure, and the residue was partitioned between water and diethyl ether. The ether phase was washed with two portions of aqueous 2% hydrochloric acid, two portions of water, two portions of aqueous 10% sodium carbonate, two portions of water and one portion of aqueous saturated sodium chloride solution in that order. The washed ethereal solution was dried over magnesium sulfate, and the ether was evaporated under reduced pressure. The oily residue was purified by column chromatography on silical gel, elution with hexane. This afforded (2,4-difluoro-[1,1'-biphenyl]-3-yl)methyl cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate (1.8 g), Example XIV in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9](C=O)[CH2:8][CH2:7]1)=O.Cl.[NH2:20][OH:21].C([O-])(=O)C.[NH4+].C(O)C>O>[Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4](=[N:20][OH:21])[CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: NO
Reactant: O=CN1CCC(C(=O)c2ccc(Cl)cc2Cl)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: ON=C(c1ccc(Cl)cc1Cl)C1CCNCC1
Yield: 27.1 %

Procedure:
A mixture of 105 g of 4-(2,4-dichlorobenzoyl)-1-formylpiperidine, 70 g of hydroxylamine hydrochloride, 135 g of ammonium acetate, 1.05 l of ethanol and 350 ml of water was stirred and heated at 130° for 40 hrs. The reaction mixture was evaporated and 2.0 l of water was added to the residue. The water was decanted from the oil and the oil was washed two times with 500 ml of water and dissolved in about 400 ml of dichloromethane. The insoluble material was collected. The dichloromethane extract was washed twice with 600 ml of water. The combined aqueous phases were made basic with potassium carbonate/water. The precipitate was filtered, washed with water and dried over phosphorus pentoxide in vacuo to yield 27.2 g (9.96%) of 4-(2,4-dichlorobenzoyl)piperidine oxime. The insoluble material was dissolved in hot water and made alkaline with potassium carbonate-water. The precipitate was filtered, washed with water and dried over phosphorus pentoxide in vacuo. The solid was dissolved in 200 ml methanol and 2 ml of conc hydrochloric acid was added. After heating for 5 mins, the solution was filtered and evaporated in vacuo to dryness. The residue was recrystallized from methanol-ether to yield product as the hydrochloride, mp 284°.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH:13](O)[C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:6]2)[CH3:2].C(N(CC)C(F)(F)C([F:25])Cl)C.C(Cl)Cl.Cl>O>[CH3:2][O:1][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([F:25])[CH:8]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:6]2.[CH3:2][O:1][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][C:14]([O-:16])=[O:15])[CH:7]=[CH:6]2
Reactant: COC(=O)C(O)C1CCc2cc(OC)ccc2C1
Reactant: CCN(CC)C(F)(F)C(F)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)CC1CCc2cc(OC)ccc2C1F
Product: COc1ccc2c(c1)C=CC(CC(=O)[O-])C2
Reaction time: 24 h

Procedure:
A mixture of 25 g. of methyl 6-methoxy1-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetate, 38 g. of 1-diethylamino-1,1,2trifluoro-2-chloroethane and 150 ml. of methylene chloride are allowed to stand for 24 hours. The fluorination reaction mixture is added to 250 ml. of water containing 12 g. of hydrogen chloride; the resulting mixture is separated and the methylene chloride phase is washed with water, dried over sodium sulfate, and evaporated to yield methyl 6-methoxy-1-fluoro-1,2,3,4-tetrahydro-2-naphthylacetate and 6-methoxy-1,2-dihydro-2-naphthylacetate. The mixture is separated on alumina eluting with acetone: diethyl ether (1:4) and the separated fractions are identified by ultraviolet spectroscopy. The fraction containing methyl 6-methoxy-1-fluoro-2-naphthylacetate is evaporated and the residue is refluxed with 23 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 500 ml. of xylene for six hours. The cooled mixture is filtered and chromatographed on alumina eluting with chloroform. The fraction containing the product is evaporated to yield methyl 6-methoxy-1-fluoro- 2-naphthylacetate.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[CH2:13]([N:1]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC[C@H](N)CO
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.9 %

Procedure:
To a stirred solution of (S)-(+)-2-aminobutan-1-ol (5 g, 56.18 mmol) in dry acetonitrile (100 ml) was added dry powdered potassium carbonate (31 g, 224.72 mmol) followed by benzyl bromide (19 g, 111.11 mmol). The reaction was stirred at room temperature for 24 h. The solvent was removed under vacuo and the residue was taken up in ethyl acetate (100 ml) and water (100 ml). The organic phase was washed again with water, dried (Na2SO4) and concentrated to provide the pure product as slightly yellow oil (14.5 g, 97.3%). δH (250 MHz, CDCl3) 0.98 (3 H, t, J 7.5, CHCH2CH3), 1.38-1.2 (1 H, m, CHCHHCH3), 1.94-1.78 (1 H, m, CHHCH3), 2.83-2.71 (1 H, m, CHCHHCH3), 3.22 (1 H, s, b, OH), 3.65-3.4 (2 H, m, CH2OH), 3.47 (2 H, d, J 17.5, 2×CHHPh), 3.94 (2 H, d, J 17.5, 2×CHHPh), 7.46-7.26 (10 H, m, 2×C6H5); δC (250 MHz, CDCl3) 139.42 (2×C), 129.1 (2×CH), 128.52 (2×CH), 127.25 (2×CH), 61.97 (CH), 60.67 (CH2), 53.23 (CH2), 17.92 (CH2), 11.83 (CH3); m/z 270.2 (M+H)
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[S:11][CH:12]=2)[N:5]=[C:4]2[C:19]3[C:25]([Br:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][C:20]=3[O:21][C:3]=12.O=P(Cl)(Cl)[Cl:31]>>[Br:26][C:25]1[C:19]2[C:4]3[C:3]([O:21][C:20]=2[CH:22]=[CH:23][C:24]=1[O:27][CH3:28])=[C:2]([Cl:31])[CH:7]=[C:6]([C:8]1[N:9]=[C:10]([NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[S:11][CH:12]=1)[N:5]=3
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2oc3c(O)cc(-c4csc(NC(=O)C(C)C)n4)nc3c2c1Br
Product: COc1ccc2oc3c(Cl)cc(-c4csc(NC(=O)C(C)C)n4)nc3c2c1Br
Temperature: 110 °C
Yield: 27 %

Procedure:
A mixture of 16C (0.7 g, 1.5 mmol) in POCl3 (10 mL) was heated to 110° C. and reacted for 30 min. TLC monitored the reaction. After the reaction completed, POCl3 in the reaction mixture was evaporated. The residue was added dropwise into ice-water. The precipitated solids were collected by filtration and purified by short column chromatography to give M16 (0.2 g, 27% yield).